Traditionally, analgesics have fallen into two broad categories. Simple, non-narcotic analgesics, such as aspirin, which appear to work by inhibition of prostaglandin synthetase, are effective against pain of integumental origin such as headache and muscle aches, but are often ineffective in controlling deeper, more intense pain. The narcotic analgesics appear to work through interaction with the endorphin-enkephalin system of the central nervous system and are useful in controlling pain which is too intense to be controlled by the weaker, non-narcotic analgesics. However, centrally-acting narcotic analgesics have several serious undesirable side effects, including the development of physical dependence and tolerance, sedation, respiratory depression, hypotension, increase in cerebrospinal fluid pressure, nausea, vomiting and constipation. Therefore, it is desirable to administer the smallest effective dose possible. In some patients, particularly the chronically ill, the narcotic side effects make it impossible to administer dosages sufficient to adequately control pain over the required time period.
This invention combines capsaicin or a capsaicin derivative with a narcotic analgesic, resulting in a synergistic increase in analgesia without a corresponding increase in side effects. This makes it possible to control pain which cannot be adequately controlled by narcotics alone due to the severity of the undesirable side effects.
It has been recently discovered that capsaicin, a natural product of certain species of the genus Capsicium, induces analgesia. Capsaicin (8-methyl-N-vanillyl-6E-nonenamide) and "synthetic" capsaicin (N-vanillyl-nonanamide) are disclosed as analgesics in U.S. Pat. No. 4,313,958, LaHann, issued Feb. 2, 1982. Analgesic activity of capsaicin has also been discussed in the chemical and medical literature, including Yaksh, et al, Science, 206, pp 481-483 (1979); Jancso, et al, Naunyn-Schmiedeberg's Arch. Pharmacol., Vol. 311, pp 285-288 (1980) and Holzer et al, Eur. J. Pharm. Vol. 58, pp 511-514 (1979). U.S. Pat. No. 4,238,505, Nelson, issued Dec. 9, 1980, discloses 3-hydroxyacetanilide for use in producing analgesia in animals. U.S. Pat. application Ser. No. 359,464, LaHann, et al, filed Mar. 18, 1982, now, U.S. Pat. No. 4,424,206, issued Jan. 3, 1984, describes hydroxyphenylacetamides with analgesic and anti-irritant activity. Similarly, analgesic and anti-irritant activity is disclosed for N-vanillylsulfonamides in U.S. Pat. No. 4,401,663, Buckwalter, et al, issued Aug. 30, 1983; N-vanillylureas in U.S. Pat. application Ser. No. 381,672, Buckwalter, et al, filed May 25, 1982, now U.S. Pat. No. 4,460,602, issued July 17, 1984; N-vanillylcarbamates in U.S. patent application Ser. No. 384,685, Buckwalter, et al, filed June 3, 1982, now U.S. Pat. No. 4,443,473, issued April 17, 1984; N-[(substituted phenyl)methyl]alkynlamides in U.S. patent application Ser. No. 514,204, Janusz, et al, filed July 14, 1983, now abandoned; methylene substituted N-[(substituted phenyl)methyl]alkanamides in U.S. Pat. application Ser. No. 514,205, Janusz, et al, filed July 14, 1983; N[(substituted phenyl)methyl]-cis-monounsaturated alkenamides in U.S. patent application Ser. No. 514,206, LaHann, et al, filed July 14, 1983, now U.S. Pat. No. 4,498,848, issued Jan. 15, 1985; and N-[substituted phenyl)methyl]diunsaturated amides in U.S. patent application Ser. No. 514,207, LaHann, et al, filed July 14, 1983, now abandoned.
None of these references, however, suggest in any way the desirability of concurrent administration of capsaicin or a capsaicin derivative and an opioid. In fact, just the opposite is suggested. Both U.S. Pat. No. 4,313,958 (LaHann) and Yaksh et al suggest that the mechanism of capsaicin-induced analgesia is totally unrelated to that of narcotic-induced analgesia. It is extremely hard to predict when a synergistic effect will be obtained from two pharmaceutical compositions which take effect through different mechanisms. Furthermore, the only references which considered the effect of capsaicin pretreatment on morphine analgesia suggest that, when young rats are pretreated with capsaicin and then injected with morphine 1-4 months later, there is generally no effect (Holzer et al), and that in some cases pretreatment with capsaicin can in fact decrease morphine analgesia (Jancso et al).
Although there are several patents which disclose analgesic compositions containing a narcotic combined with another analgesic compound, none of these compounds has a structure at all similar to that of capsaicin. See U.S. Pat. Nos. 4,404,210, Schmidt, issued Sept. 13, 1983; 4,083,981, Yamamoto, issued April 11, 1978; 4,315,936, Capetola et al, issued Feb. 16, 1982; 4,379,789, Capetola et al, issued April 12, 1983.
Thus, based on the art, one would have expected the combination of capsaicin or a capsaicin analog with an opioid analgesic to produce no enhancement of the analgesic effect at best, and at worst, an antagonistic response. Yet, surprisingly, it has now been found that such a combination results in a synergistic increase in analgesia.